The proposed NCDDG research program involves the investigation of the mechanisms that lead to lymphoma and leukemia to further our understanding of human disease and develop new therapies. The central focus of the group is ont he interaction of the cytokine IL-7 and its cognate receptor Il-7R. Signals transmitted to lymphoid cells via the IL-7/IL-7R interaction have profound biological effects. B and T cell precursors are stimulated to grow by Il-7 and certain T cells become activated. IL-7 appears to be a central signaling molecule in lymphocyte mediated immunity and has been shown to have several biological properties, most notably the ability to induce tumor immunity. However, persistent signaling via the IL-7R can lead to malignant transformation and the development of leukemia and lymphoma in mice. There is a growing body of evidence that similar mechanisms may be involved in human lymphoid neoplastic diseases. In an effort to elucidate the role of Il-7 in normal and malignant cells, transgenic mice were engineered to produce Il-7 in lymphoid cells that are highly sensitive to this factor. These mice develop a syndrome of lymphoproliferation that leads to lymphomas and a cutaneous infiltration of T cells. The proposed research program will utilize these mice as a model of human disease for the development of new therapeutic compounds for lymphoid cancers (leukemias and lymphomas). In a further effort to clarify the role of IL-7 in lymphoid function and model human disease, new lines of transgenic mice will be generated that express IL-7 in various subsets of T cells.